(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a prostate cancer poster session. Dr. Christopher Sweeney presented the results of an analysis evaluating early changes in circulating tumor DNA (ctDNA) tumor fraction as a ‘value add’ to prostate-specific antigen (PSA) for predicting early progression in metastatic castrate-resistant prostate cancer (mCRPC) patients.
IMbassador250 (NCT03016312) was a prospective phase III trial which showed no overall survival benefit for atezolizumab addition to enzalutamide for abiraterone pre-treated mCRPC patients.1 An ad hoc analysis of IMbassador250 has previously demonstrated that baseline tumor fraction levels and a 75% reduction in tumor fraction both to be prognostic of survival outcomes in these patients. In this analysis, Dr. Sweeney and colleagues evaluated whether the early detection of and changes in ctDNA tumor fraction are associated with clinical survival outcomes.
Pre-study treatment (i.e., post-abiraterone, but pre-atezolizumab/enzalutamide) plasma samples from IMbassador250 were profiled using FoundationOne Liquid CDx (F1LCDx). To enable tumor-naïve ctDNA monitoring while avoiding non-tumor signaling, Dr. Sweeney and colleagues developed FoundationOne Monitor (F1M), which leverages the same sequencing platform as F1LCDx and enables quantification of and changes in ctDNA tumor fraction from prior F1LCDx or F1M results. Changes in tumor fraction status (i.e., detected versus not detected) between baseline and cycle 3, day 1, as well as detection at C3D1 alone, were correlated with radiographic progression-free survival (rPFS) and overall survival (OS), as well as changes in serum PSA levels (50% reduction).
This analysis included a total of 418 patients with advanced mCRPC. The median patient age was 70 years, and the median baseline serum PSA level was 68.7 ng/ml. The median baseline tumor fraction level was 15.5%. At baseline, 355 (80%) patients had detectable tumor fraction levels, whereas 303 (72%) had detectable tumor fraction levels at cycle 3, day 1.
Detection of tumor fraction levels at cycle 3, day 1 was associated with significantly worse rPFS (HR: 3.24, 95% CI: 2.46 – 4.28, p<0.001) and OS (HR: 5.03, 95% CI: 3.41 – 7.41, p<0.001). Patients with tumor fraction detected at both baseline and cycle 3 day 1 had median rPFS of 4.1 months and a median OS of 12.6 months. 88% of patients with “ctDNA detected” at cycle 3, day 1 had an rPFS ≤6 months.
The positive predictive value of ctDNA status for the prediction of a non-durable response was 74%, compared to 67% for PSA. When tumor fraction and PSA reduction at cycle 3 day 1 were discordant (i.e., tumor fraction detected but PSA levels reduced and vice versa), patients with [undetectable tumor fraction/PSA not reduced] had more favorable outcomes compared to [PSA reduced/tumor fraction detected] patients (median OS: 22.1 months versus 16 months, p<0.001).
Tumor fraction also provided additional risk stratification for patients with clinically ambiguous results who had absence of radiographic progression, but concurrently did not achieve a >50% PSA reduction, resulting in high- and low-risk populations (median OS: 13 months versus 20.5 months, HR=3.80, p<0.001).
Dr. Sweeney concluded that this new tumor-naïve monitoring assay (F1M) for molecular response assessment allows for ctDNA tumor fraction detection and evaluation of corresponding dynamics. Tumor fraction detection at cycle 3 day 1 was linked to unfavorable outcomes and identified early progression post-abiraterone, with increased information derived from tumor fraction detection at baseline. Tumor fraction detection with this assay complements PSA testing, which had a lower positive predictive value for identifying early progression compared to ctDNA. Together, this provides a non-invasive strategy that is independent of and additive to PSA, allowing for a refined, personalized approach tailored to the individual patient’s risk of progression.
Presented by: Christopher Sweeney, MBBS, Professor, Medical Oncology, South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024